The prototype atypical neuroleptic, clozapine, is notable for its enhanced therapeutic effects in-otherwise treatment resistant patients with schizophrenia. We observed in our initial study that over a third of patients respond more favorably to clozapine than to the typical neuroleptic, fluphenazine. We have focused on mechanisms of action of the atypical neuroleptic by addressing clozapine's diverse pharmacologic effects using an array .of biological techniques. We observed in vivo "markers" of dopaminergic antagonist effects, serotonergic antagonist effects and enhancement of norepinephrine function. Predictors of clozapine response include high EPS during typical neuroleptic treatment, low plasma HVA during clozapine treatment and enhanced serotonergic responsivity in a drug-free state. We have now replicated the initial clinical findings in a second cohort of 18 patients studied under this crossover design. In addition to confirming the enhanced efficacy of clozapine, the combined sample provides unique opportunity to investigate antidepressant and other therapeutic effects of clozapine. Studies of mechanism of clozapine's anti psychotic action utilizing SPECT and PET imaging techniques are described in Projects Z01-MH02350 and Z01-MH- 02653.